EP2403536A1 - Administration par voie orale de médicaments hydrophiles pour le cerveau - Google Patents

Administration par voie orale de médicaments hydrophiles pour le cerveau

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Publication number
EP2403536A1
EP2403536A1 EP10707342A EP10707342A EP2403536A1 EP 2403536 A1 EP2403536 A1 EP 2403536A1 EP 10707342 A EP10707342 A EP 10707342A EP 10707342 A EP10707342 A EP 10707342A EP 2403536 A1 EP2403536 A1 EP 2403536A1
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EP
European Patent Office
Prior art keywords
composition according
drug
group
enkephalin
leucine
Prior art date
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Granted
Application number
EP10707342A
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German (de)
English (en)
Other versions
EP2403536B1 (fr
Inventor
Ijeoma Uchegbu
Andreas Schatzlein
Aikaterini Lalatsa
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University College London
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School of Pharmacy University of London
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Publication of EP2403536A1 publication Critical patent/EP2403536A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
    • A61K47/6935—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/70—Nanostructure
    • Y10S977/773—Nanoparticle, i.e. structure having three dimensions of 100 nm or less
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/70—Nanostructure
    • Y10S977/788—Of specified organic or carbon-based composition
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/902—Specified use of nanostructure
    • Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/915—Therapeutic or pharmaceutical composition

Definitions

  • the present invention relates to a new system for the oral delivery of hydrophilic drugs.
  • the system involves forming an endogenously cleavable lipophilic derivative of the hydrophilic drug, and formulating this with an amphiphilic compound.
  • the invention has particular utility for the oral delivery of hydrophilic drugs to the brain.
  • BBB blood brain barrier
  • Capillary endothelial cells are characterised by tight intercellular junctions, low pinocytotic activity and efflux transporters at their luminal surface. All of these features limit the passage of most molecules into the brain.
  • Prior brain targeting strategies have involved: a) exploiting endogenous transporters for carrier mediated uptake (e.g. monoclonal antibody - drug conjugates or monoclonal antibody - particle conjugates) to exploit the human insulin or transferrin receptor (Pardridge 2007; Beduneau et al. 2008); b) the inhibition of ABC transporters [e.g. P-glycoprotein (Bihorel et al. 2007) and breast cancer resistance protein (Deeken and Loscher 2007)]; c) the use of surfactant coated poly(butylcyanoacrylate) nanoparticles (Kreuter et al. 2003); and d) the use of cationic carriers such as cationic albumin (Lu et al. 2006) and cationised forms of drug molecules (Girod et al. 1999).
  • endogenous transporters for carrier mediated uptake e.g. monoclonal antibody - drug conjugates or monoclonal antibody - particle conjugates
  • ABC transporters e
  • peptide drugs are large in comparison to the vast majority of non- peptide drugs. They typically have molecular weights in excess of 500 Da, which means that diffusion across biological barriers is slow, resulting in poor oral absorption into the blood stream. They are usually hydrophilic and have a significant potential to form hydrogen bonds in aqueous environments. In addition, they often contain several ionisable groups and hence are typically charged at physiological pH. Peptides are also susceptible to degradation within the gastrointestinal tract by carboxy peptidases and amino peptidases. When taken in combination, these factors mean that unmodified peptides are typically very poor candidates for oral delivery, based upon structure alone. Furthermore peptides, even if absorbed are susceptible to degradation within the blood with half lives of a few minutes. Furthermore hydrogen bond formation by hydrophilic peptides limits their transport across the blood brain barrier making neuroactive peptides very difficult to deliver via the oral route.
  • a wide variety of drug delivery vehicles are known. These include, for instance, liposomes, which are composed of a phospholipid bilayer that may act as a carrier for both hydrophilic and hydrophobic drugs.
  • WO03/033027 teaches the use of cationic dendrimers (for instance, poly(propylenimine) dendrimers with a diaminobutane core) to deliver bioactive molecules such as polynucleotides or polypeptides to a human or animal recipient.
  • WO2004/026912 describes solubilising polysaccharides which are used to solubilise hydrophobic drugs.
  • the polysaccharides are amphiphilic and are generally selected from any derivatives of the following: chitosans, dextrans, alginic acids, starches, dextran and guar gums. GCPQ and GCHQ are used in the Examples of this patent application as solubilising polysaccharides.
  • WO2008/017839 describes micellar clusters formed from amphiphilic carbohydrate polymers and their use in formulating hydrophobic drugs. Palmitoyl glycol chitosan is a specifically exemplified amphiphilic carbohydrate polymer.
  • the Patent Application focuses on improved drug delivery to the CNS or cornea. Gastrointestinal delivery of the drugs is briefly mentioned.
  • Amphiphilic polymers such as poly(ethylenimine) polymers are used.
  • Leucine [5] -Enkephalin a hydrophilic peptide was modified by making it more lipophilic.
  • a lipid ester pro-drug of Leucine I5] -Enkephalin was formed and added to a composition comprising quaternary ammonium palmitoyl glycol chitosan (GCPQ).
  • GCPQ quaternary ammonium palmitoyl glycol chitosan
  • the composition was delivered intravenously.
  • the prodrug was converted to Leucine [5] -Enkephalin in vivo.
  • the lipid ester prodrug with GCPQ was shown to result in significantly higher Leucine [5] -Enkephalin brain levels than when Leucines-Enkephalin alone or Leucine [5] -Enkephalin with GCPQ after LV. administration were used.
  • composition comprising a lipophilic derivative of a hydrophilic drug and an amphiphile compound for use in therapy wherein the composition is orally administered to the human or animal body.
  • a pharmaceutical composition suitable for oral administration comprising a lipophilic derivative of a hydrophilic drug, an amphiphile compound, and one or more pharmaceutically acceptable excipients.
  • lipophilic is meant a compound having very low solubility in water ( ⁇ 0.1mg/mL).
  • hydrophilic is meant a compound with high water solubility (>1 mg/mL).
  • the invention has particular utility for the delivery of hydrophilic drugs to the brain.
  • the drug, delivered in accordance with the invention is able to cross the blood brain barrier and have a therapeutic effect in the brain.
  • the lipophilic derivative of the hydrophilic drug typically comprises a hydrophilic drug and a cleavable linker.
  • the derivative may act as a pro-drug which is cleaved to the active drug in the human or animal body, preferably at the drug's target location.
  • the linker is a moiety which is linked to the hydrophilic drug and is cleavable from it.
  • the linker is enzymatically cleavable.
  • local environmental conditions within the body may alternatively promote cleavage.
  • Low pH, in the range 1 - 5, and hypoxic conditions are known to promote prodrug cleavage.
  • the linker is hydrophobic and renders the hydrophilic drug lipophilic.
  • the linker is a substituted or unsubstituted hydrocarbon group comprising at least 4 carbon atoms, and comprises, for instance a C 4 - 30 alkyl group, a C 4-30 alkenyl group, a C 4-30 alkynyl group, a C 5-20 aryl group, a multicycle hydrophobic group with more than one C 4- C 8 ring structure such as a sterol (e.g.
  • a multicyclic hydrophobic group with more than one C 4 - Ce heteroatom ring structure a polyoxa CrC 4 alkylene group such as polyoxa butylene polymer, or a hydrophobic polymeric substituent such as a poly (lactic acid) group, a poly(lactide-co-glycolide) group or a poly(glycolic acid) group.
  • the linker may be linear, branched or cyclo groups.
  • the linker is covalently attached to the hydrophilic drug.
  • the linker is attached to the hydrophilic drug by means of an acyl group.
  • the linker may be attached via an ester or an amide linkage, with the nitrogen or oxygen atom of this linkage derived from the hydrophilic drug.
  • the hydrophilic drug may have an amine or a hydroxyl group which is derivatised by the linker.
  • the hydrophilic drug is a peptide, such groups may form part of the peptide backbone or of an amino acid's side chain.
  • a particularly preferred linker is derived from palmitic acid, i.e. a palmitoyl group.
  • Other preferred linkers are derived from caprylic, capric, lauric, myristic, stearic and arachidic acids and cholesterol.
  • the hydrophilic drug is preferably a peptide.
  • Peptides are of tremendous clinical value for the treatment of many central nervous system (CNS) disorders, and preferably therefore the drug is a CNS active drug.
  • Many existing peptide pharmaceuticals are rendered ineffective after oral administration or are unable to cross the blood brain barrier (BBB) mainly due to their hydrophilicity, size, charge and rapid metabolic degradation in the gastrointestinal tract and blood, as detailed above.
  • the hydrophilic drug is preferably a neuroactive agent.
  • Endogenous opioid neuropeptides, preferably neuropentapeptides are particularly preferred drugs for use in this invention. Examples include Met 5 - Enkephalin and Leu 5 -Enkephalin.
  • the drug may be used to treat brain disorders such as schizophrenia, obsesity, pain and sleep disorders, psychiatric diseases, neurodegenerative conditions, brain cancers and infective diseases.
  • Preferred drugs include neuropeptides: enkephalin, neuropeptide S, dalargin, orexin, vasopressin, leptin, cholecystokinin, dynorphin, detorphin I, oxytocin, vancomycin, gentamicin, tobramycin and doxycycline.
  • a lipophilic prodrug, palmitoylated Leucine [5] -Enkephalin (TPLENK), comprising a cleavable ester bond susceptible to blood esterases is an example of a lipophilic derivative of a hydrophilic drug which can be used in this invention.
  • amphiphile compounds used in this invention are compounds comprising a hydrophobic moiety covalently linked to a hydrophilic moiety and are typically selected from the following compounds: sorbitan esters, polysorbates, poly(ethylene glycol) alkyl, aryl and cholesterol ethers [e.g. phenolic and alkyl derivaties of poly(ethylene glycol)], poly(ethylene oxide) - polypropylene oxide) block copolymers, polymer amphiphiles, phospholipids, fatty acid salts, acylated amino acids, alkyl quaternary amine salts, alkyl amine oxides, alkyl sulphonates, aryl sulphonates, C 4 - C 30 alkyl amine salts.
  • the amphiphile compound is an amphiphilic carbohydrate compound.
  • amphiphilic carbohydrate compound is typically selected from chitosans, dextrans, alginic acids, starches, guar gums, and their derivatives.
  • amphiphilic compound is a chitosan.
  • amphiphilic carbohydrate compound is represented by the formula:
  • a + b + c 1.000 and a is between 0.01 and 0.990, b is between 0.000 and 0.980, and c is between 0.01 and 0.990; and wherein:
  • X is a hydrophobic group
  • Ri, R 2 and R 3 are independently selected from hydrogen or a substituted or unsubstituted alkyl group
  • R 4 , R 5 and R 6 are independently selected from hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, or a substituted or unsubstituted alkene group;
  • R 7 may be present or absent and, when present, is an unsubstituted or substituted alkyl group, an unsubstituted or substituted amine group or an amide group; or a salt thereof.
  • the a, b and c units may be arranged in any order and may be ordered, partially ordered or random.
  • the * in the formula is used to indicate the continuing polymer chain.
  • the molar proportion of the c units is greater than 0.01, and more preferably is at least 0.110, more preferably is at least 0.120, more preferably is at least 0.150 or in some embodiments is at least 0.18, Generally, the molar proportion of the c unit is 0.400 or less, and more preferably is 0.350 or less.
  • the molar proportion of the a unit is between 0.010 and 0.800, and more preferably between 0.050 and 0.300.
  • the molar proportion of the b unit is between 0.200 and 0.850, and more preferably between 0.200 and 0.750.
  • the b units may optionally be absent.
  • the c units provide the first portion of the monomer units that are derivatised with a hydrophobic group, and the a units provide the second portion of the monomer units and are derivatised with a quaternary nitrogen group.
  • the b units provide the third group of monomer units in which the amine groups are derivatised in a different manner to the first or second group, or else are underivatised.
  • the hydrophobic group X is preferably selected from a substituted or unsubstituted group which is an alkyl group such as a C 4-30 alkyl group, an alkenyl group such as a C 4-30 alkenyl group, an alkynyl group such as a C 4-30 alkynyl group, an aryl group such as a C 5-20 aryl group, a multicycle hydrophobic group with more than one C 4- C 8 ring structure such as a sterol (e.g.
  • a multicyclic hydrophobic group with more than one C 4 - C 8 heteroatom ring structure a polyoxa CrC 4 alkylene group such as polyoxa butylene polymer, or a hydrophobic polymeric substituent such as a poly (lactic acid) group, a poly(lactide-co-glycolide) group or a poly(glycolic acid) group.
  • the X groups may be linear, branched or cyclo groups. Any of the X groups may be directly linked to the c unit (i.e.
  • a particularly preferred class of X substituents are linked to the chitosan monomer unit via an amide group, for example as represented by the formula CH 3 (CHa) n CO-NH-, where n is between 2 and 28.
  • amide groups are produced by the coupling of carboxylic acids to the amine group of chitosan.
  • Ri, R 2 and R 3 are preferably independently selected from hydrogen or a substituted or unsubstituted alkyl group such as a C 1-I0 alkyl group. Where Ri, R 2 and/or R 3 are aikyl groups, they may be linear or branched. Preferably, Ri, R 2 and R 3 are independently selected from hydrogen, methyl, ethyl or propyl groups.
  • R 4 , R 5 and R 6 present on the C6 or the sugar units are independently selected from hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, or a substituted or unsubstituted alkene group.
  • Preferred R 4 , R 5 and R 6 groups are substituted with one of more hydroxyl groups, or another non-ionic hydrophilic substituent.
  • the R 7 group may be present or absent in the general formula. When absent, it provides a quaternary ammonium functional group that is directly linked to the chitosan ring of the a monomer unit. When the R 7 group is present it may be a unsubstituted or substituted alkyl group (e.g. a C M0 alkyl group) for example as represented by the formula -(CH 2 J n -, an amine group as represented by the formula -NH-(CH 2 ) n -, or an amide group as represented by the formula -NH-CO-(CH 2 ) n -, where n is 1 to 10 and is preferably 1 to 4.
  • a C M0 alkyl group e.g. a C M0 alkyl group
  • R 7 N + R 1 R 2 R 3 substituent is provided by coupling betaine (-OOC-CH 2 -N-(CH 3 ) 3 ) to the amine substituent of the a unit providing an amide group such as in betaine, -NH-CO-CH 2 -N + R 1 R 2 R 3 .
  • substituents described herein may be either unsubstituted or substituted with one or more additional substituents as is well known to those skilled in the art.
  • substituents include halo; hydroxyl; ether (e.g., Ci -7 alkoxy); formyl; acyl (e.g.
  • C 3-2O heterocyclyl including, e.g., C 5-20 carboaryl, C 5-20 heteroaryl, C 1-7 alkyl-C 5-20 aryl and C 5-20 haloaryl) groups.
  • ring structure as used herein, pertains to a closed ring of from 3 to 10 covalently linked atoms, yet more preferably 3 to 8 covalently linked atoms, yet more preferably 5 to 6 covalently linked atoms.
  • a ring may be an alicyclic ring, or aromatic ring.
  • alicyclic ring as used herein, pertains to a ring which is not an aromatic ring.
  • carrier ring refers to a ring wherein all of the ring atoms are carbon atoms.
  • carrier ring refers to an aromatic ring wherein all of the ring atoms are carbon atoms.
  • heterocyclic ring as used herein, pertains to a ring wherein at least one of the ring atoms is a multivalent ring heteroatom, for example, nitrogen, phosphorus, silicon, oxygen or sulphur, though more commonly nitrogen, oxygen, or sulphur.
  • the heterocyclic ring has from 1 to 4 heteroatoms.
  • the above rings may be part of a "multicyclic group”.
  • compositions of the present invention may form particulate aggregates. These may be formed by the aggregation of individual amphiphile molecules and the lipophilic derivative of the hydrophilic drug and have a mean particle size between 20nm and 20 ⁇ m.
  • the mean particle size can readily be determined microscopically or by using photon correlation spectroscopy and is conveniently determined in aqueous dispersions prior to filtration.
  • the polymeric micellar aggregates have a minimum mean particle size of at least 100nm, and more preferably at least 175nm, and a maximum mean particle size which is preferably 10 ⁇ m or less. After filtration, the mean particle size typically reduces to a preferred range between about 100nm and 500nm.
  • the ratio of amphiphile compound to drug is within the range of 1 :10-20:1 ; a preferred range is 1 :1 -10:1 and a more preferred ratio is 5:1 by weight.
  • the ratio of amphiphile compound to drug to pharmaceutically acceptable carrier may be about 1 - 5 mg: 1mg : 1g.
  • the pharmaceutical composition of this invention may be in the form of any of the following: tablets, liquid capsules, or powder form.
  • typically used carriers include sucrose, lactose, mannitol, maltitol, dextran, corn starch, typical lubricants such as magnesium stearate, preservatives such as paraben, sorbin, anti-oxidants such as ascorbic acid, alfa-tocopheral, cysteine, disintegrators or binders.
  • effective diluents include lactose and dry corn starch.
  • Liquids for oral use include syrups, suspensions, solutions and emulsions, which may contain a typical inert diluent used in this field, such as water.
  • the composition may contain sweetening and/or flavouring agents.
  • a suitable daily dose can be determined based on age, body weight, administration time, administration method, etc. While the daily doses may vary depending on the condition and body weight of the patient, and the nature of the drug, a typical oral dose is about 0.1-2mg/person/day, preferably 0.5-
  • Figure 1 shows palmitoylation of Fmoc protected Leucine 151 - Enkephalin using Palmitic acid N-Hydroxysuccinimide ester;
  • Figure 2 shows a synthetic scheme for Quaternary ammonium Palmitoyl Glycol Chitosan
  • Figure 3 shows the in vivo concentration of Leucine [51 -Enkephalin following oral administration
  • TFA can also cleave the side-chain protecting group as well as the solid-support. Evaporation and removal of acetic acid as an azeotrope with hexane or evaporation of TFA resulted in reduced volume of a suspension containing the crude peptide.
  • the crude peptide (LENK) was precipitated with (frozen, -2O 0 C) diethyl ether, collected with centrifugation (1500 rpm at 4 0 C for 45minutes) three times (with syringing and discarding the supernatant and further washing with frozen diethyl ether after the first two centrifugations), dried with nitrogen, dissolved in water and lyophilised.
  • the overall yield of the reaction was between 92-99%.
  • Triethylamine (350 ⁇ l, 2.5mmol) was added to a solution of FMOC-Tyr- (OH)-Gly-Gly-Phe-Leu-2-CI-Trt-Resin (O.immol) in DMF (8mL) and the resultant suspension was reacted with the N-hydroxysuccinimide ester of palmitic acid (176.75mg, 0.5mmol, PNS) in DMF (5ml_) at 25 0 C (constant temperature room or water bath) for 24 h, during which time the suspension was agitated (120 rpm). The mixture was then concentrated in vacuo to remove volatile products and then was redissolved in DMF (4mL).
  • Figure 1 illustrates the synthetic process.
  • the redissolved product still on the resin was filtered and washed with copious amounts of DMF.
  • the product bound to the resin was treated with 20% piperidine in DMF (2OmL) for 20-25 minutes.
  • cleavage of the peptide chain from the resin was performed with the acetic acid cleavage mixture (AcOH/TFE ⁇ /DCM - 2:2:6) for 2 hours (Barlos et al. 1991) at room temperature as stated above.
  • Figure 1 shows palmitoylation of Fmoc protected Leucine [5] -Enkephalin using PNS.
  • RP-HPLC Semi-preparative reverse-phase high performance liquid chromatography
  • the mobile phase consisted of 82% 25mM ammonium bicarbonate buffer and 18% acetonitrile. Unless otherwise indicated, samples were detected at 280nm. The retention time was 7.1 minutes for Leucine [5] -Enkephalin and 8.3 minutes for TPLENK Peptide Characterisation:
  • the peptides were characterised by Electrospray ionisation (positive/negative) mass spectrometry, analytical reverse phase HPLC, nuclear magnetic resonance (NMR) spectrometry, Fourier transform infra-red (FTIR) spectroscopy, X-ray powder diffraction, transmission electron microscopy and photon correlation spectroscopy.
  • Figure 2 which shows a synthetic scheme for quaternary ammonium palmitoyl glycol chitosan. Acid Degradation of Glycol Chitosan
  • glycol chitosan The acid degradation of glycol chitosan was carried out as described earlier (Wang et al. 2001).
  • Glycol chitosan (2g) was dissolved in hydrochloric acid (4M, 15OmL) and the solution filtered to remove insoluble impurities (if required).
  • the (filtered) solution was placed in a preheated water bath at 5O 0 C. At 24 hours the reaction was stopped and the product was removed from the water bath.
  • Molecular weight was controlled by degradation time, i.e. increasing the acid degradation time decreased the molecular weight of the resulting polymer.
  • Quaternisation was carried out using essentially the same method as reported by Domard and others (Domard et al. 1986; Uchegbu et al. 2001) with modifications (Qu et al. 2006). Briefly palmitoyl glycol chitosan (300mg) was dispersed in N-methyl-2-pyrrolidone (25mL) overnight for 12 hours at room temperature.
  • the quaternary ammonium product was precipitated with diethyl ether (40OmL), filtered and washed twice more with copious amounts of diethyl ether (twice with 30OmL) to give a light brown hygroscopic solid.
  • the quatemised product was dissolved in water (100ml) to give a yellow solution.
  • the resultant solution was exhaustively dialysed against water (5L) with six changes over a 24h period and the dialysate was passed through a column (1 x 6 cm) packed with Amberlite IRA-96 Cl "1 .
  • the column was packed with one volume of the resin (3OmL) and subsequently washed with hydrochloric acid solution (9OmL, 1M) followed by deionised water (10L) to give a neutral pH.
  • the clear eluate from the column was freeze-dried to give quaternary ammonium palmitoyl glycol chitosan (GCPQ) as a transparent fibrous solid.
  • the synthetic yield of GCPQ is between 115-134mg (i.e. 38.3 - 44.6%).
  • Self assembled polymer amphiphiles were prepared by vortexing (WhirliMixer, Fisherbrand) of GCPQ (2.3mg or 5 mg) in double-deionised water (1mL) and then by probe sonicating (MSE Soniprep 150) with the instrument set at 50% of its maximum output for 8 minutes on ice. Particle size was measured by Photon correlation spectroscopy (Malvern Zetasizer 3000HS A , Malvern Instruments, UK) at 25 0 C at a wavelength of 633nm and the data analysed using the Contin method of data analysis. Polymer solutions were left for 15 min at room temperature (25 0 C) before particle sizing was done.
  • Polymer dispersions 75 mg mL "1 ) with Leucine [5] -Enkephalin (LENK) (15 mg mL “1 ) or Palmitoylated Leucine [5] -Enkephalin (TPLENK) (15 mg mL “1 ) were prepared by vortexing (WhirliMixer, Fisherbrand) for 5 minutes in double de- ionised filtered [0.2 ⁇ m, 33mm Millex GP syringe driven filter unit, polyether sulphone (PES) membrane for sterilisation of aqueous solutions] water (pH 6.4), followed by probe sonication (MSE Soniprep 150) with the instrument set at 50% of its maximum output for 15 minutes on ice. Formulations were not filtered.
  • the resulting particulate formulations were imaged using scanning electron microscopy (SEM).
  • SEM scanning electron microscopy
  • Fresh samples were mounted on a standard SEM sample holder and were fixed on a brass/aluminium stub using double sided carbon impregnated adhesive discs.
  • the sample was then sputter coated with a conducting gold-palladium (10nm, 60% gold-palladium) coating using a SEM coating system for 2 minutes at 30 mA (Emitech K550 Sputter Coater, Emitech Limited, Ashford, UK, Deposition range: 0-5OmA, Deposition rate: 0-25nm rnin "1 , Sputter timer: 0-4 min, Vacuum Pump: 85 lit min "1 , room temperature) before viewed and photographed under a range of magnifications under high vacuum using Philips XL 30 ESEM FEG scanning electron microscope.
  • SEM scanning electron microscopy
  • samples were detected at 280nm.
  • the flow rate was set at 1 mL min "1 at 35°C and an injection volume of 40 ⁇ L was used.
  • the retention time was 11.5 minutes for Leucines- Enkephalin and 14.0 minutes for TPLENK and the lowest detection limits were 1 ⁇ g mL "1 and 10 ⁇ g mL "1 for Leucine [51 -Enkephalin and TPLENK respectively.
  • Empower software I was used for data analysis. Results
  • ICR ICR
  • mice Male outbred mice (18-24g, 4 weeks old, Harlan, Oxon, UK) were used.
  • the animals were housed in groups of 5 in plastic cages in controlled laboratory conditions with ambient temperature and humidity maintained at -22 0 C and 60% with a 12-hour light and dark cycle (lights on at 7:00 and off at 19:00).
  • Food and water were available ad libitum and the animals acclimatised for 5-7 days prior to any experiments in the Animal House, School of Pharmacy, University of London (London, UK). Animals were fasted overnight for oral delivery experiments. Animals were only used once and were acclimatised at the testing environment for at least 1 hour prior to testing. All experiments were performed in accordance with the recommendations and policies of the Home Office (Animals Scientific Procedures Act 1986, UK) and the Ethics Committee of the School of Pharmacy, University of London guidelines for the care and use of laboratory animals.
  • Double de- ionised filtered (0.2 ⁇ m, 33mm Millex GP syringe driven filter unit, PES membrane for sterilisation of aqueous solutions) water was used as the disperse phase for the oral formulations.
  • Final formulation concentration of Leucines- Enkephalin was 15mg mL "1 with a ratio of peptide to polymer 1: 5 w/w. All formulations were prepared by vortexing (WhirliMixer, Fisherbrand) and then by probe sonication (MSE Soniprep 150) with the instrument set at 50% of its maximum output for 15 minutes on ice. The formulations were left overnight in the fridge; the administered volume was set to a maximum of 0.2ml per mouse. The administered volume was adjusted based on the HPLC quantification of LENK and TPLENK and the body weight of each animal. The maximum volume was dosed for placebo (H 2 O) receiving mice.
  • the peptides were analysed by reversed phase high-performance liquid chromatography on a reversed phase Waters Sunfire C18 column (5 ⁇ m, 4.6mm X 250mm) with a guard column attached [Waters Sunfire C18 (5 ⁇ m, 4.6mm X 10mm)], using a Waters TM 515 HPLC pump connected to a Water TM 717 plus Autosampler with a Waters TM 486 Tunable Absorbance Detector.
  • the mobile phase consisted of 82% 5OmM acetate buffer and 18% acetonitrile (pH 5.8). Unless otherwise indicated, samples were detected at 280nm.
  • the flow rate was set at 1mL min "1 at 35 0 C for analytical runs and the injection volume at 40 ⁇ L.
  • the retention time was 11.5 minutes for Leucine [5] -Enkephalin and 14.0 minutes for TPLENK and the lowest detection limits were 1 ⁇ g mL "1 and 10 ⁇ g mL "1 for Leucine [5] -Enkephalin and TPLENK respectively.
  • Empower software I was used for data analysis.
  • Blood samples (0.4 - O. ⁇ mls per mouse) were collected into a chilled syringe and transferred into evacuated sterile spray coated (with tripotassium ethylenediamine tetraacetic acid - 3.6mg) medical grade PET tubes (3 x 75mm K3E Vacutainer ⁇ , BD Biosciences, UK) and maintained on ice (4 0 C) until centrifugation. There is no dilution effect in spray coated tubes.
  • Plasma was obtained as the supernatant after centrifugation of blood samples at 1 ,60Og or 4800rpm for 15 minutes at 4 0 C with a Hermle Z323 centrifuge (Hermle Laborteschink GmbH, Germany) and was pipetted into 1.5mL centrifuge tubes and stored at -7O 0 C for later use.
  • Hermle Z323 centrifuge Hermle Laborteschink GmbH, Germany
  • the homogenate was transferred in 15ml_ centrifuge tubes and was centrifuged to remove any debris at 9,000 rpm for 20 minutes at 4 0 C with a Hermle Z323 centrifuge (Hermle Laborteschink GmbH, Germany). The pellet was discarded and the supernatant stored in glass 14ml_ vials was frozen (-20 0 C) and lyophilised. The lyophilised samples were stored at -8O 0 C for later use.
  • the lyophilised brain homogenate samples were reconstituted with 1 mL of Reagent A (1% Trifluoroacetic acid) vortexed and centrifuged at 13,000 rpm for 20 minutes (MicroCentaur, MSE, London, UK). 100 ⁇ L of plasma after thawing and 100 ⁇ L of Reagent A were centrifuged at 13,000 rpm for 20 minutes (MicroCentaur, MSE, London, UK) to acidify the plasma sample and remove interfering proteins.
  • Reagent A 1% Trifluoroacetic acid
  • C18 silica solid phase extraction columns (Waters SEP- PAK, 200mg C18, Bachem, UK) were equilibrated with 1mL of Reagent B (60% Acetonitrile, 1 % Trifluoroacetic acid and 39% distilled water) and washed with 9mL of Reagent A. 300 ⁇ L of the supernatant of the reconstituted brain homogenate and the supernatant of the plasma without the pellet were loaded onto the equilibrated column. Then, the columns were washed with 6 mL of Reagent A and the washings were discarded. The peptides were eluted with 3m L of Reagent B and collected in a 5m L polypropylene tube.
  • Reagent B 50% Acetonitrile, 1 % Trifluoroacetic acid and 39% distilled water
  • HPLC quantitation of the peptide content of the formulations was for L, LG and PG for oral administration 99.9%, 99.1% and 98.9% respectively.
  • the plasma concentration of Leucine [5] -Enkephalin following oral administration peaked at 1 hour for L and LG formulations (L: 29.3 ng 10 '1 mL '1 and LG: 26.6 ng 10 '1 mL “1 ) and 30 minutes for PG (17.1 ng 10 '1 mL 1 ) and at 4 hours in the brain tissue for all three formulations (L: 0.695 ng g ' ⁇ LG: 1.090 ng g " ⁇ PG: 1.098 ng g "1 ).
  • the AUC (0-1440) in the brain increased by 1.7 fold for both nanoparticulate formulations (LG and PG) when compared to levels obtained with Leucines-Enkephalin alone.
  • Leucines-Enkephalin causes central analgesic effects in the brain with slight preference for ⁇ -opioid receptor. Occurrence of central analgesic effects would prove the brain targeting of LENK-GCPQ particulate formulations and TPLENK-GCPQ particulate formulations in accordance with the preliminary pharmacokinetic data.
  • LENK and water have been used as controls. LENK alone was used in order to observe the equipotent effect of this peptide in the same dose as in the particulate formulation and water as a placebo to rule out the plausible effects of endogenously produced neuropeptides during antinociception testing. Animals
  • ICR CD-1 male outbred mice (22-28g, 4-5 weeks old, Harlan, Oxon, UK) were used.
  • the animals were housed in groups of 5 in plastic cages in controlled laboratory conditions with ambient temperature and humidity maintained at -22 0 C and 60% with a 12-hour light and dark cycle (lights on at 8:00 and off at 20:00). Food and water were available ad libitum and the animals acclimatised for 5-7 days, prior to any experiments, in the Animal House, School of Pharmacy, University of London (London, UK). Animals were fasted overnight for oral delivery experiments. Animals were only used once and were acclimatised at the testing environment for at least 20 hours prior to testing.
  • the dose administered corresponded to 70 mg Kg '1 and 100 mg Kg "1 after oral gavage for Leucines- Enkephalin (L and LG) and TPLENK (PG) respectively.
  • Double de-ionised filtered (0.2 ⁇ m, 33mm Millex GP syringe driven filter unit, PES membrane for sterilisation of aqueous solutions) water was used as the disperse phase.
  • the final formulation concentration of both peptides was 15mg mL '1 with a ratio of peptide to polymer of 1 : 5 w/w. All formulations were prepared by vortexing (WhirliMixer, Fisherbrand) and then by probe sonication (MSE Soniprep 150) with the instrument set at 50% of its maximum output for 15 minutes on ice. The formulations were left overnight in the fridge.
  • the administered volume was set to a maximum of 0.2ml per mouse.
  • the administered volume was adjusted based on HPLC quantitation of LENK and TPLENK and the body weight of each animal. The maximum volume was dosed for placebo (H 2 O) receiving mice.
  • Antinociception Studies Antinociception was assessed in mice using the tail flick warm water bioassay (D'Amour and Smith 1941 ; Mogil et al. 1999). The protruding distal half of the tail (4 - 5cm) of confined mice in a Plexiglas restrainer was immersed in circulating warm water maintained at 55 0 C ⁇ 0.1 0 C (Tjolsen and Hole 1993; PoIt et al. 1994) by a thermostatically controlled water bath (W14, Grant Instruments, Cambridge Ltd, Herts, UK).
  • thermometer Gallenkamp, Griffin, THL- 333-020L, 76 mm x 1mm, UK.
  • the response latency times, in centiseconds, recorded for each mouse to withdraw its tail by a "sharp flick" were recorded using a digital stopwatch capable of measuring 1/100th of a second.
  • the first sign of a rapid tail flick was taken as the behavioural endpoint which followed in most cases 1-3 slow tail movements.
  • Three separate withdrawal latency determinations (separated by > 20sec) were averaged (PoIt et al. 1994) and individual time points were at least 10 minutes apart.
  • Average baseline latency was determined to be 2.33 ⁇ 0.70 (Mean ⁇ SD) sec. Maximal possible latencies were reached for none, one, six and nine mice out of 16 for H 2 O (0%), L (6.25%), LG (37.5%) and PG (56.25%) respectively.
  • the number of analgesic responders (defined as one whose response was 2 or more times the value of the baseline latency) was none, five, thirteen and fifteen out of 16 for H 2 O (0%), L (31.25%), LG (81.25%) and PG (93.75%) respectively.
  • Statistically significant differences (p ⁇ 0.05) were observed between PG versus
  • the ANOVA statistically different groups are: * :p ⁇ 0.05 vs H 2 O, +: p ⁇ 0.05 vs Leucines- Enkephalin, #:p ⁇ 0.05 vs Leucine 151 -Enkephalin - GCPQ. References

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Abstract

La présente invention concerne une composition comprenant un dérivé lipophile d'un médicament hydrophile et un composé amphiphile destiné à être utilisé en thérapie, la composition étant administrée par voie orale au corps humain ou animal. L'invention concerne des dérivés tels que la leucine[5]-encéphaline palmitoylée et est utile dans le traitement de la schizophrénie, de l'obésité, de la douleur et des troubles du sommeil, de maladies psychiatriques, de troubles neurodégénératifs, de cancers du cerveau et de maladies infectieuses.
EP10707342.1A 2009-03-02 2010-03-01 Administration par voie orale de médicaments hydrophiles pour le cerveau Active EP2403536B1 (fr)

Applications Claiming Priority (3)

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GBGB0903559.3A GB0903559D0 (en) 2009-03-02 2009-03-02 Oral delivery of hydrophilic drugs to the brain
US12/420,896 US8278277B2 (en) 2009-03-02 2009-04-09 Delivery of hydrophilic drugs
PCT/GB2010/050355 WO2010100479A1 (fr) 2009-03-02 2010-03-01 Administration par voie orale de médicaments hydrophiles pour le cerveau

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GB201011602D0 (en) * 2010-07-09 2010-08-25 Univ London Pharmacy Delivery of hydrophilic peptides
US20140249090A1 (en) * 2011-04-01 2014-09-04 Max-Planck-Gesellschaft zur Förderung der Wissenschaft e.V. Peptides and pharmaceutical compositions for use in the treatment by nasal administration of patients suffering from anxiety and sleep disorders
WO2014152497A2 (fr) 2013-03-15 2014-09-25 The Trustees Of Columbia University In The City Of New York Ostéocalcine en tant que traitement de troubles cognitifs
GB201319437D0 (en) 2013-11-04 2013-12-18 Nanomerics Ltd Delivery of drugs
US10525099B2 (en) * 2014-10-01 2020-01-07 Oxytone Bioscience B.V. Orally disintegrating solid pharmaceutical dosage unit containing a partus control substance
HUE051974T2 (hu) 2014-10-01 2021-04-28 Oxytone Bioscience B V Szájban szétesõ, szülést szabályozó ágenst tartalmazó, szilárd halmazállapotú gyógyászati dózisegység
WO2016081728A1 (fr) 2014-11-19 2016-05-26 The Trustees Of Columbia University In The City Of New York Ostéocalcine comme traitement de fragilité associée au vieillissement

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US6703381B1 (en) * 1998-08-14 2004-03-09 Nobex Corporation Methods for delivery therapeutic compounds across the blood-brain barrier
GB0125216D0 (en) 2001-10-19 2001-12-12 Univ Strathclyde Dendrimers for use in targeted delivery
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CA2754140C (fr) 2019-02-19
GB0903559D0 (en) 2009-04-08
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EP2403536B1 (fr) 2021-11-17

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